STUDIES ON THE FUNCTIONAL ROLE OF DA D4 RECEPTORS IN RODENT BRAIN DA D4 receptors (D4R) are concentrated at relatively high levels in prefrontal cortex, striatum, hippocampus/amygdala, and cerebellum where they are believed to regulate both glutamate and GABA neurons with a preferential location in GABA interneurons. Polymorphisms in D4R have been associated with ADHD and also substance use disorders. It is thus hypothesized that D4R modulate neuronal networks by controlling the activity of local inhibitory interneurons. However, the role of D4R in brain function is still not properly understood. Here we have taken a brain imaging strategy to assess the role of D4R in the sensitivity to rewarding effects of drugs and natural reinforcers. The following summarizes results from two different experimental strategies to investigate the D4R Role of D4R in baseline brain metabolism (marker of brain function) and in response to methylphenidate. Methods: We compared brain glucose metabolism (measured with micro-positron emission tomography and (18)F2-fluoro-2-deoxy-D-glucose) at baseline and after methylphenidate (10 mg/kg, i.p.) in mice with genetic deletion of D4R (D4R KO). Results: At baseline the D4R KO had lower metabolism in prefrontal cortex (PFC) and greater metabolism in the cerebellar vermis (CBV) than wildtype;when given MP, D4R KO increased metabolism in PFC and decreased it in CBV, whereas wildtype mice decreased metabolism in PFC and increased it in CBV. Conclusion: These findings corroborate the relevance of D4R in modulating PFC and CBV activity at baseline as well as its reactivity to stimulant drug administration. Interestingly the modulation of PFC appears to be opposite of that to the CBV, which could reflect the differential role of inhibitory interneurons in these brain regions. Both structural and functional abnormalities in PFC and CBV have been documented in ADHD and thus the association of ADHD with D4R may reflect the role of these receptors in modulating activity of these regions. They may also help explain the differences in responses to MP between patients with ADHD and healthy controls and between patients with ADHD with different D4R polymorphisms. Role of D4R in modulating the rewarding and locomotor effects of stimulant drugs Role of D4R on operant responding for food or cocaine Methods: To assess the involvement of D4R on operant responding for food or cocaine we compared wild-type mice D4R KO mice on a fixed-ratio 1 (FR1) schedule during a session that lasted 90 min Results: There were no differences in D4R KO and wildtype in responding for food pellets or for intravenous cocaine. Conclusion: Our findings suggest that the D4R is not directly involved in mediating operant response behaviors for food or cocaine. Note that these results are consistent with previous findings with cocaine in conditioned place preference (CPP) and locomotor responses that showed no differences between wildtype and KO. However we cannot rule out the possibility that a different operant schedule may have uncovered differences between the strains. STUDIES ON THE EFFECTS OF PHYSICAL ACTIVITY ON DRUG REWARD Physical activity (exercise) may be beneficial in the prevention of substance use disorders;however, the extent to which physical activity can interfere with the reinforcing effects of drugs during the adolescent period, which is a period of great vulnerability for drug experimentation, has not been fully evaluated. Here, we assess the effects of chronic forced exercise during adolescence on preference for cocaine. Methods: Here we compared conditioned place preference (CPP) to cocaine between sedentary and physically active rats (males and females). The physically active rats were exposed to a treadmill for 6 weeks on a progressive time-increased schedule for up to 1 h of running per day, whereas the sedentary rats remained in their home cage. CPP was measured at the end of the 6 week period. Results: Chronic exercise significantly attenuated cocaine CPP in both males and females compared to sedentary rats. Male exercised rats did not show cocaine CPP and female exercised rats showed significantly reduced cocaine CPP compared to the female sedentary rats. Females had greater cocaine CPP than males overall. Conclusion: These findings show evidence that physical activity interfered with conditioned response to cocaine in adolescent rats. Thus strategies to promote physical activity during adolescence should be evaluated with respect to their potential protective effects against substance use disorders. We also corroborate a gender-specific sensitivity to the conditioning effects of cocaine (females >males), that highlights the need to consider gender-tailored interventions for drug abuse prevention. STUDIES ON THE INVOLVEMENT OF THE DA SYSTEM IN FOOD REGULATION AND OBESITY Leptin regulates neural circuits controlling feeding behaviors, metabolism, locomotor activity and body weight, and the absence of leptin produces profound obesity. Some of these effects involve leptins modulation of the DA mesoaccumbens pathway. DA neurons express leptin receptors and also receive projections from leptin receptor containing neurons in the lateral hypothalamus. Leptin deficient mice showed decreased DA release in striatum and decrease response to stimulant drugs. Here we assess the effects of leptin deficiency on basal D2R-binding in the brain and the effects of leptin treatment. Methods: We compared D2R binding between ob/ob mice, which have a mutation in the leptin gene that prevents its expression, and wild type mice both at baseline and after leptin treatment. Basal striatal D2R binding were measured with autoradiography using 3H spiperone as the radioligand. Results: Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Basal striatal D2R binding did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Conclusion: These findings provide evidence that leptin modulates D2R expression in striatum which could underlie the decrease sensitivity to stimulant drugs shown by leptin deficient mice. The findings also document a genotype-dependent effects of leptin treatment in D2R expression.